Fat for heat

Description The distinct properties of brown adipose tissue may be harnessed to mitigate obesity The global prevalence of obesity has nearly tripled since the 1970s. According to the latest World Health Organization (WHO) Global Health Observatory data, more than 39% of adults (∼1.9 billion people), are overweight, with at least 2.8 million people dying yearly as a result of being overweight or obese (1–3).


DISTINCT FUNCTIONS FOR FAT
Adipose tissue can be divided into two functionally and morphologically distinct types: white adipose tissue (WAT) and brown adipose tissue (BAT). The two tissue types have markedly different functions: WAT preserves energy for future use through lipid storage, whereas BAT generates heat through nonshivering thermogenesis.
Active BAT is common in human newborns and infants, but only recently have we become aware of its presence in some adults. BAT can be activated by cold exposure or adrenergic receptor agonists (5)(6)(7), suggesting the possibility that BAT could be activated to restore energy balance in overweight individuals (4). Yet only a small proportion of adults possess active BAT, limiting the applicability of any potential therapeutic approaches.

COMING OUT OF THE COLD
We investigated the regulatory circuits of human BAT to ascertain whether certain clinical parameters are distinct among individuals with active BAT. To aid our investigation, we retroactively analyzed fluorodeoxyglucose ( 18 F) positron emission tomography integrated with computed tomography ( 18 F-FDG PET/CT) scans of 8440 individuals performed for various diagnostic reasons from 2007 to 2015 (8). 18 F-FDG PET/CT scans-commonly used in oncology and able to detect BAT-revealed a correlation between the season of an individual's conception and their propensity to form active BAT. Individuals with active BAT were more likely to have been conceived during a colder month (8). However, given the retrospective nature of our inquiry and potential confounding factors, causality could not be inferred.
To confirm the durability of this correlation and determine whether a causal mechanism could be established, we used mouse model systems to investigate the effect of parental cold exposure (CE) on offspring BAT activity. We found that parental CE for 7 days before conception or during gestation resulted in higher thermogenic activity in offspring. An in vitro fertilization system further revealed that the effects of parental CE are transmitted though the paternal lineage in sperm, suggesting an intergenerational regulatory axis connecting ambient temperature, germline epigenetic transmission, and BAT. Our focus thus shifted to studying this unknown mechanism of coldinduced epigenetic programming in BAT.
Using a series of adrenergic agonist and antagonist analyses as well as a brown celldepletion mouse model, we identified that either genetically depleting brown adipocytes or pharmacologically inhibiting b3-adrenergic receptor (ADRB3) erased the impact of paternal CE in the offspring (8). We then performed whole-genome bisulfite sequencing of sperm and transcriptomic analyses of BAT. Principal components analysis revealed distinct clustering through paternal CE and DNA methylation, and RNA-sequencing data suggested enhanced neuronal development in BAT, which was functionally confirmed by an increased release of norepinephrine in paternal CE offspring.
Our results indicate that paternal CE induces epigenetic programming of the sperm, leading to offspring that possess hyperactive BAT and an improved adaptation to hypothermia. These mechanisms form the rationale for designing therapies and personalized strategies to induce BAT functionality, to counteract obesity and comorbid diseases (9).  (11). It is possible to analyze adipose tissue at single-cell resolution (12,13). However, this approach is technically challenging for lipid-laden adipocytes, which are highly variable in size, have low density, and are delicate in nature (14). To overcome these limitations, I developed a fat-specific single-nucleus RNA-sequencing method compatible with frozen, archived clinical adipose tissue samples (15).

FLEXIBLE PHENOTYPES
By resolving the cellular compositions and dynamics of BAT in mice and in humans, we identified a rare adipocyte population, P4 cells (see the figure), that increases in abundance at higher temperatures and decreases in cold conditions. Immunostaining and electron microscopy confirmed the transcriptionally defined P4 cell type in vivo, which exhibited both multilocular and unilocular morphology, with randomly oriented cristae in their mitochondria (15).
Alterations in the structure of mitochondria are likely to compromise the function of these cells, and we hypothesized that they are associated with observed changes in BAT activity. We found that the loss of aldehyde dehydrogenase 1A1 (Aldh1a1) expression, which is exclusively expressed in P4 cells, promoted BAT function and protected mice from becoming obese.
Although there are only a small number of P4 cells, this finding suggests that they may play a regulatory role in modulating wholeorgan thermogenesis. Additionally, we observed that acetate, a molecular inhibitor of brown adipocyte thermogenesis mediated by G protein-coupled receptor 43, is reduced in cells that do not express Aldh1a1 (15).

FUELING FUTURE THERAPIES
The study of BAT is an expanding field, focused on harnessing thermogenic tissue as a potential tool for mitigating obesity. Unveiling the critical regulatory elements in adipose tissue will help us to make the greatest use of BAT.
My work identifies epigenetic regulations and local modulations of BAT as mechanisms that contribute to the control of thermogenesis. Looking ahead, I hope that we and others can demonstrate that targeting thermogenic adipose tissue is a promising therapeutic intervention for obesity. Our work presents the first single-cell map for human BAT, identifies regulatory circuits in the adipose tissue microenvironment for modulating adipocyte thermogenesis, and opens a new avenue to harness brown fat in our efforts to address obesity. j